Childhood obesity is a large and growing problem in the United States. NIDA has made a commitment to supporting obesity research because of overlaps in addiction and compulsive eating, including neural mechanisms. The proposed studies aim to characterize newly identified hypothalamic genetic factors that may put adolescents at risk for decreased metabolic rate and obesity in an effort to understand the neurobiology of obesity risk and to identify therapeutic targets for obesity early in life. The objective of the proposed studies is to investigate genetic factors that contribute to diet-induced obesity risk early in life. Decreased metabolic rate in juveniles in response to maternal high-fat diet is hypothesized to promote excess body fat accumulation, which may lead to persistent obesity in adulthood even with later normalization of food intake and metabolism. Specific Aim 1 tests the effects of reducing or increasing expression of newly identified genes on energy expenditure and adiposity in rats selectively bred to be resistant to diet-induced obesity (DR rats). Experiments will determine if the genes are causally related to maternal diet-induced obesity risk in DR rats. Specific Aim 2 will characterize expression and functional relevance of the genes in outbred Sprague-Dawley rats. Experiments will determine if the same genes are overexpressed in outbred Sprague-Dawley rats with maternal high-fat diet history, will localize gene expression and determine neuronal type within the lateral hypothalamus, and will determine the effects of gene knockdown and knocking. The results will demonstrate the functional significance of hypothalamic genes newly identified to be differentially expressed in relation to risk for diet-induced obesity. PUBLIC HEALTH RELEVANCE: Obesity rates in American children and adolescents have doubled and tripled in the last 30 years, leading to increased risk for obesity in adulthood, initiating a life-long struggle to lose weight. A better understanding of genetic and environmental factors that contribute to obesity in children is needed. The proposed studies seek to determine the relevance of genes newly identified to be associated with maternal diet-induced obesity risk in young offspring in order to identify therapeutic targets for early-life obesity.